NMDA receptor activation modulates evoked release of substance P from rat spinal cord

The possible modulation exerted by glutamate on substance P (SP) release from the rat spinal cord has been investigated. The N‐methyl‐ D ‐aspartate (NMDA) receptor agonist, NMDA (1 μ M ), increased SP basal outflow by 46.5 ± 10.9% ( n =3, P <0.01) without changing the evoked release of the peptide. Conversely, NMDA antagonists but not 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) inhibited both electrically‐evoked and capsaicin‐induced release of SP. In particular, D‐2‐amino‐5‐phosphonopentanoate (D‐AP5; 50 μ M ) inhibited electrically‐evoked and capsaicin‐induced release of SP by 93 ± 2.4% and 93.2 ± 3.8% ( n =12, P <0.01), respectively. Functional pharmacological evidence is provided for glutamate exerting a positive feedback on SP release evoked by C fibre stimulation via NMDA receptor activation.